Process for preparing filled hard-shell capsules with (meth)acrylate copolymer based coatings with a capsule-filling machine

ABSTRACT

A process can be used for preparing a polymer coated hard-shell capsule, filled with a fill containing a biologically active ingredient. The hard-shell capsule contains a body and a cap, and in a closed state, the cap overlaps the body either in a pre-locked state or in a final-locked state. The material of the body and the cap contains an ethyl-, methyl-, or propyl-ether of cellulose, starch, or pullulan. The hard-shell capsule is coated with a coating layer that covers the hard-shell capsule in the pre-locked state. The coating layer contains one or more (meth)acrylate copolymers, where the coating layer is present in an amount of about 1 to 5.8 mg/cm2. The process involves providing the polymer-coated hard-shell capsule in the pre-locked state to a capsule-filling machine, separating the body and the cap, filling the body with the fill, and rejoining the body and the cap in the final-locked state.

FIELD OF THE INVENTION

The invention is in the field of processes for preparing filledpolymer-coated hard-shell capsules with a capsule filling machine.

TECHNICAL BACKGROUND

U.S. Pat. No. 4,138,013 describes hard-shell capsules with entericproperties. The hard-shell capsules comprise telescopically engaged bodyand cap portions. The capsule body and cap portions are formed bydip-molding using a homogeneous film-forming mixture, comprisingpolymers selected from hydroxypropyl methyl cellulose (HPMC), a mixtureof (1) hydroxypropyl methyl cellulose and an ammonium salt of celluloseacetate phthalate or (2) gelatin and an ammonium salt of a copolymer of(meth)acrylic acid and methacrylic acid alkyl ester. The capsules itselfhave already enteric properties without applying a further entericcoating layer.

Xujin Lu and Pankaj Shah, “Dissolution of Gelatin Capsules: Evidence andConfirmation of Crosslinking” in Dissolution technologies August 2017,6-20. The authors discuss that crosslinking is a common problem in thedissolution of gelatin capsules.

A. A. Atama (2007) “Polyelectrolyte Complexes od EUDRAGIT® L30 D-55 andGelatin, Antinociceptive Activity of Entrapped Piroxicam”. The authordiscusses the interaction of EUDRAGIT® L 30 D-55 and gelatin. EUDRAGIT®L 30 D-55 is a 30% aqueous dispersion of an anionic copolymer based onmethacrylic acid and ethyl acrylate. Gelatin type A is generated by acidpretreatment of pig skin. The isoelectric point (IEP) of gelatin isbetween 7-9. Below pH 8 gelatin A is positively charged and can interactwith negatively charged EUDRAGIT® L 30 D-55.

Huyghebaert et al., European Journal of Pharmaceutical Sciences 21(2004)617-623, describe an alternative method for the enteric coating ofcapsules made of HPMC in which ready-to-use enteric capsule parts areobtained. It is reported that, in contrast to gelatine capsules, HPMCcapsules can be enteric coated relatively easily from aqueouspreparations. However, it is necessary to additionally apply a sealingbetween the capsule halves, e.g. through a gelatine solution to beapplied manually, in order to avoid a leakage of the capsule and anuncontrolled escape of the contents in the stomach. Another technique isto apply water/ethanol mixtures between the capsule halves and to weldthe parts together at 40-80° C. Using aqueous preparations (EUDRAGIT® FS30 D, EUDRAGIT® L 30 D-55) based on (meth)acrylate copolymers orpolyvinyl acetate phthalate, plasticizers such as triethyl citrate andfurther auxiliaries, such as, for example, talc, it is possible toprovide HPMC capsules with an enteric film from separately coated bodiesand caps. A separate sealing step can be prevented in the case of thisformulation process. In particular, HPMC capsules which have been coatedwith (meth)acrylate copolymers are depicted as particularly advantageousin the sum of their properties.

WO 2011/012369A1 describes a coating composition for the enteric coatingof capsule halves made of water-soluble or water-swellable polymermaterial.

JP2003-325642A describes a hard, empty capsule with enteric solubilityand a manufacturing method for such a hard, empty capsule. The capsulecap is coupled with the capsule body in the semi-locked state and anenteric solubility membrane is formed on the entire surface. Then thecapsule cap is removed from the capsule body and the contents arefill-packed. The parts are then coupled in a locked state. This allowsto avoid the application of a coating after the filling of the capsule,which would add a thermal burden to the content. Also, a seal stickersealing of the capsule after filling can be avoided, since there is anoverlap of the coating in the locked state, which seals the gap betweenthe capsule cap and capsule body. The capsule may be filed with thedesired content such as propolis, raw royal jelly, black-vinegarextract. The capsules as described are made from gelatin by a dipcoating procedure by immersing metallic molds into a gelatin and waterdispersion. The metallic molds are pulled up, rotated, cooled and dried.Thereby, cylindrical membranes are formed in uniform thickness, cut inthe dimensions as required as a capsule caps or as capsule bodies.Capsule caps and capsule bodies are coupled in a semi-locked state. Anenteric soluble substance may be applied by spray coating.

The enteric soluble substance according to JP2003-325642A may be a plantor animal protein originating in wheat, a soybean, a collagen, gelatin,etc., cellulose-acetate phthalate, a cellulose acetate succinate,cellulose acetate maleate, hydroxypropyl methyl cellulose phthalate,hydroxypropyl-methylcellulose acetate succinate, polyvinyl-acetatephthalate, polyvinyl butyrate phthalate. The amount of coating is morethan the quantity performed by conventional enteric solubility capsuleformation, 20 to 80 by weight %, 40 to 60 by weight % desirable. Thefilm thickness is about 0.1 to about 0.5 mm. These film thicknesses arelarger than the tolerance variation of the outer diameter of the capsulebody and the internal diameter of the capsule cap.

JP S81-221117A describes an enteric hard capsule formation to be used,for example. In the medical field. The capsules are coated in apre-locked state before filling to avoid the drawbacks of conventionalhard capsules coated with enteric solvent after filling, e.g. losses ofexpensive medicines. The coating in the pre-locked state results in apartial overlap of the body with the cap that has a sufficient buckingeffect to prevent gastric juices from entering into the capsule from thefitting part of the cap and the body. The invention uses ordinarygelatin capsules that may be of the so-called locking method of“snap-fit”. As enteric solvents hydroxypropyl methyl cellulosephthalate, hydroxypropyl methyl cellulose acetate phthalate, celluloseacetate phthalate and methacrylic acid-methyl methacrylate copolymersmay be used. In the examples capsules of size No. 1 were coated with 14and 38 mg hydroxypropyl methyl cellulose phthalate (HP-55, Shin-EtsuChemical Co., Ltd). It was found that 18 mg per capsule with a filmthickness of around 80 μm was preferable. JP S61-221117A mentionsmethacrylic acid-methyl methacrylate copolymers as further possiblecoatings.

SUMMARY OF THE INVENTION

Hard-shell capsules which are enteric coated in a pre-locked state,opened, filled with a fill and are then closed to a final-locked stateare in principle known from JP2003-325842A and JP S61-221117A. Bothcitations describe the use of gelatin capsules which tend to crossinking during storage (Xujin Lu and Pankaj Shah, “Dissolution of GelatinCapsules: Evidence and Confirmation of Crosslinking” in Dissolutiontechnologies August 2017, 6-20). The gelatin capsules are pre-coatedwith a coating zein (JP2003-325642A) or hydroxypropyl methyl celluloseacetate phthalate (HP-55 JP2003-325642A).

The use of enteric coated capsules in a pre-locked state seems to beadvantageous since the application of additional sealing steps asdiscussed in Huyghebaert et al. (European Journal of PharmaceuticalSciences 21 (2004) 617-423) can be avoided. Also, a thermal burden forthe fill that takes place when the coating is applied after the filling,can be avoided by means of coating in the pre-locked state beforecapsule filling.

For industrial scale production a high turnover and output process isdesirable. Such high turnover and output can be achieved by use ofautomated capsule-filling machines. Half and fully automated capsulefilling machines can process provided capsules which are already coatedin the pre-locked state and rapidly perform the steps of separating thebody and the cap, filling the body with the fill and rejoining the bodyand the cap in the final-locked state. A fully automated machine iscapable to run at a speed of 1,000 or even a much more higher number ofprocessed capsules per hour. The high speed however causes highmechanical stress to the pre-locked capsules and especially to themechanical resistance of the coatings. Therefore, there is a need toprovide a process, which allows the processing of capsules coated in apre-locked state in a capsule filling machine without Impairingproperties such as resistance in acidic medium (less than 10% activeingredient release at pH 1.2 in 120 min) and rapid dissolution at higherpH (pH 5.5 or above, pH 6.8).

The invention is concerned with a process for preparing a polymer coatedhard-shell capsule, filled with a fill comprising a biologically activeingredient, wherein the hard-shell capsule is comprising a body and acap, wherein in a closed state the cap overlaps the body either in apre-locked state or in a final-locked state, wherein the material of thebody and the cap comprises an ethyl-, methyl- or propyl-ether ofcellulose, starch or pullulan, wherein the hard-shell capsule is coatedwith a coating layer that covers the hard-shell capsule in thepre-locked state, wherein the coating layer is comprising one or more(meth)acrylate copolymer(s), wherein the coating layer is present in anamount of about 1 to 5.8 mg/cm², preferably 2 to 5 mg/cm², wherein adried film with a thickness of 250 μm, corresponding to the compositionof the coating layer, shows an elongation at break of about 15 to 500,preferably 50 to 450%, wherein the polymer-coated hard-shell capsule isprovided in the pre-locked state to a capsule-filling machine, whichperforms the steps of separating the body and the cap, filling the bodywith the fill and rejoining the body and the cap in the final-lockedstate.

Biologically Active Ingredient

The process as disclosed refers to a polymer coated hard-shell capsule,filled with a fill comprising a biologically active ingredient. Abiologically active ingredient may be defined as an ingredient that mayafter delivery or intake confers a preventive or therapeutical effect inan animal or human body. The biologically active ingredient ispreferably a pharmaceutically active ingredient and/or a nutraceuticallyactive Ingredient.

Pharmaceutically or Nutraceutically Active Ingredients

The invention is preferably useful for immediate, enteric or sustainedrelease formulated pharmaceutical or nutraceutical dosage forms with afill-in of pharmaceutically or nutraceutically active ingredients.

Suitable therapeutic and chemical classes of pharmaceutically activeingredients which members may be used as fill-in for the describedpolymer-coated hard-shell capsules are for instance: analgesics,antibiotics or anti-infectives, antibodies, antiepileptics, antigensfrom plants, antirheumatics, benzimidazole derivatives, beta-blocker,cardiovascular drugs, chemotherapeutics, CNS drugs, digitalisglycosides, gastrointestinal drugs, e.g. proton pump inhibitors,enzymes, hormones, liquid or solid natural extracts, oligonucleotides,peptide hormones proteins, therapeutic bacteria, monoclonal microbials,microbial components, peptides, proteins and their (metal)salts i.e.aspartates, chlorides, orthates, urology drugs, vaccines.

Further examples of drugs that may be used as fill-in for the describedpolymer-coated hard-shell capsules are for instance acamprosat, aescin,amylase, acetylsalicylic acid, adrenalin, 5-amino salicylic acid,aureomycin, bacitracin, balsalazine, beta carotene, bicalutamid,bisacodyl, bromelain, budesonide, calcitonin, carbamacipine,carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycetin,cimetidine, cisapride, cladribine, clorazepate, cromalyn,1-deaminocysteine-8-D-arginine-vasopressin, deramciclane, detirelix,dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalisglycosides, dihydrostreptomycin, dimethicone, divalproex, drospirenone,duloxetine, enzymes, erythromycin, esomeprazole, estrogens, etoposide,famotidine, fluorides, garlic oil, glucagon, granulocyte colonystimulating factor (G-CSF), heparin, hydrocortisone, human growthhormone (hGH), ibuprofen, ilaprazole, insulin, Interferon, Interleukin,Intron A, ketoprofen, lansoprazole, leuprolidacetat lipase, lipoic acid,lithium, kinin, memantine, mesalazine, methenamine, milameline,minerals, minoprazole, naproxen, natamycin, nitrofurantion, novobiocin,olsalazine, omeprazole, orothates, pancreatin, pantoprazole,parathyroidhormone, paroxetine, penicillin, perprazol, pindolol,polymyxin, potassium, pravastatin, prednisone, preglumetacin progabide,pro-somatostatin, protease, quinapril, rabeprazole, ranitidine,ranolazine, reboxetine, rutosid, somatostatin streptomycin, subtilin,sulfasalazine, sulphanilamide, tamsulosin, tenatoprazole, trypsine,valproic acid, vasopressin, vitamins, zinc, including their salts,derivatives, polymorphs, isomorphs, or any kinds of mixtures orcombinations thereof.

It is evident to a skilled person that there is a broad overlap betweenthe terms pharmaceutically and nutraceutically active ingredients,excipients and compositions respectively a pharmaceutical or anutraceutical dosage form. Many substances listed as nutraceuticals mayalso be used as pharmaceutical active ingredients. Depending on thespecific application and local authority legislation and classification,the same substance may be listed as a pharmaceutically or anutraceutically active ingredient respectively a pharmaceutical or anutraceutical composition or even both.

Nutraceuticals are well known to the skilled person. Nutraceuticals areoften defined as extracts of foods claimed to have medical effects onhuman health. Thus, nutraceutical active ingredients may displaypharmaceutical activities as well: Examples for nutraceutically activeingredients may be resveratrol from grape products as an antioxidant,soluble dietary fiber products, such as psyllium seed husk for reducinghypercholesterolemia, broccoli (sulphane) as a cancer preservative, andsoy or clover (isoflavonoids) to improve arterial health. Thus, it isclear that many substances listed as nutraceuticals may also be used aspharmaceutically active ingredients.

Typical nutraceuticals or nutraceutically active ingredients that may beused as fill-in for the described polymer-coated hard-shell capsules mayalso include probiotics and prebiotics. Probiotics are livingmicroorganisms believed to support human or animal health when consumed.Prebiotics are nutraceuticals or nutraceutically active ingredients thatinduce or promote the growth or activity of beneficial microorganisms inthe human or animal intestine.

Examples for nutraceuticals are resveratrol from grape products,omega-3-ratty acids or (pro)anthocyanines, for instance from blueberriesor black currents, as antioxidants, soluble dietary fiber products, suchas psyllium seed husk for reducing hypercholesterolemia, broccoli(sulphane) as a cancer preservative, and soy or clover (isoflavonoids)to improve arterial health. Other examples for nutraceuticals areflavonoids, antioxidants, alpha-linoleic acid from flax seed,beta-carotene from marigold petals or anthocyanins from berries.Sometimes the expressions neutraceuticals or nutriceuticals are used assynonyms for nutraceuticals.

Preferred biologically active ingredients are metoprolol, mesalamine andomeprazole.

Polymer Coated Hard-Shell Capsule

The invention is concerned with a process for preparing a polymer-coatedhard-shell capsule, comprising a body and a cap. In the closed state thecap overlaps the body either in a pre-locked state or in a final-lockedstate. The hard-shell capsule is usually commercially available in thepre-locked state and then preferably spray-coated with a coatingsolution or dispersion comprising one or more (meth)acrylatecopolymer(s) to create a coating layer which covers the outer surface ofthe hard-shell capsule in the pre-locked state.

Hard-Shell Capsules

Hard-shell capsules for pharmaceutical or nutraceutical purposes arewell known to a skilled person. A hard-shell capsule is a two-pieceencapsulation capsule comprising of the two capsule halves, called thebody and the cap. The capsule body and cap material is usually made froma hard and sometimes brittle material. The hard-shell capsule comprisesa body and a cap. Body and cap are usually of a one end open cylindricalform with closed rounded hemispherical ends on the opposite end. Theshape and size of the cap and body are such that the body can be pushedtelescopically with its open end into the open end of the cap.

The body and the cap comprise a potential overlapping matching area(overlap area) outside the body and inside the cap which partiallyoverlap when the capsule is closed in the pre-locked state and totallyoverlap in the final-locked state. When the cap is partially slid overthe overlapping matching area of the body the capsule is in thepre-locked state. When the cap is totally slid over the overlappingmatching area of the body the capsule is in the final-locked state. Themaintenance of the pre-locked state or of the final-locked state isusually supported by snap-in locking mechanisms of the body and the capsuch as matching encircling notches or dimples, preferably elongateddimples.

Usually the body is longer than the cap. The outside overlapping area ofthe body can be covered by the cap in order to close or to lock thecapsule. In the closed state the cap covers the outside overlap area ofthe body either in a pre-locked state or in a final-locked state. In thefinal-locked state the cap covers the outside overlap area of the bodyin total, in the pre-locked state the cap overlaps the outsideoverlapping area of the body only partially. The cap can be slid overthe body to be fixed in usually one of two different positions in whichthe capsule is closed either in a pre-locked state or in a final-lockedstate.

Hard-shell capsules are commercially available in different sizes.Hard-shell capsules are usually delivered as empty containers with thebody and cap already positioned in the pre-locked state and on demand asseparate capsule halves, bodies and caps. The pre-locked hard-shellcapsules can be provided to a capsule-filling machine, which performsthe opening, filling and closing of the capsules into the final-lockedstate. Usually hard-shell capsules are filled with dry materials, forinstance with powders or granules comprising a biologically activeingredient.

The cap and body are provided with closure means that are advantageousfor the pre-locking (temporary) and/or final locking of the capsule.

Therefore, elevated points may be provided on the inner wall of the capand somewhat larger indented points are provided on the outer wall ofthe body, which are arranged so that when the capsule is closed theelevations fit into the indentations. Alternatively, the elevations maybe formed on the outer wall of the body and the indentations on theinner wall of the cap. Arrangements in which the elevations orindentations are arranged in a ring or spiral around the wall are alsopossible. Instead of the point-like configuration of the elevations andindentations, these may encircle the wall of the cap or body in anannular configuration, although advantageously recesses and openings areprovided which enable an exchange of gases into and out of the capsuleinterior.

One or more elevations may be provided in an annular arrangement aroundthe inner wall of the cap and the outer wall of the body such that, inthe final-locked position of the capsule, an elevation on the cap islocated adjacent to an elevation on the body. Sometimes elevations areformed on the outside of the body close to the open end and indentationsare formed in the cap close to the open end such that the elevations onthe body latch into the indentations in the cap in the final-lockedposition of the capsule. The elevations may be such that the cap can beopened in the pre-locked state at any time without damage to the capsuleor, alternatively, so that once it has been closed the capsule cannot beopened again without destroying it.

Capsules with one or more such latching mechanisms (latches, forinstance two circulating grooves) are preferred. More preferred arecapsules with at least two such latching means which secure the twocapsule parts to different degrees. In a part of this kind, a firstlatching (dimples or circulating notches) means may be formed close tothe openings in the capsule cap and the capsule body and a secondlatching (circulating notches) can be shifted somewhat further towardsthe closed end of the capsule parts. The first latching means secure thetwo capsule parts less strongly than the second does. This variant hasthe advantage that after the production of the empty capsules thecapsule cap and capsule body can Initially be pre-locked joined togetherusing the first latching mechanism. In order to fill the capsule, thetwo capsule parts are then separated again. After filling, the twocapsule parts are pushed together until the second set of latches firmlysecures the capsule parts in a final-locked state.

Preferably, the body and the cap of the hard-shell capsule arecomprising each encircling notches and/or dimples in the area, where thecap can be slid over the body. Encircling notches of the body anddimples of the cap match to each other to provide a snap-in or snapinto-place mechanism. The dimples may be circular or elongated (oval) inthe longitudinal direction.

Encircling notches of the body and encircling notches of the cap(closely matched rings) also match to each other to provide a snap-in orsnap into-place mechanism. This allows the capsule to be closed by asnap-into-place mechanism either in a pre-locked state or in afinal-locked state.

Preferably, matching encircling notches of the body and elongateddimples of the cap are used to fix the body and the cap to each other inthe pre-locked state. Matching encircling notches of the body and thecap are preferably used to fix or lock the body and the cap to eachother in the final-locked state.

The area where the cap can be slid over the body may be called theoverlapping area of the body and the cap or briefly the overlap area. Ifthe cap overlaps the body only partially, maybe to 20 to 90 or 80 to 85%of the overlap area, the hard-shell capsule is only partially closed(pre-locked).

Preferably, in the presence of a locking mechanism, like matchingencircling notches and/or dimples in body and cap, the partially closedcapsule may be called pre-locked. When the capsule is polymer-coated inthe pre-locked state the coating will cover the completely outer surfaceIncluding that part of the overlap area of the body and cap that is notoverlapped by the cap in this pre-locked state. Men the capsule ispolymer-coated in the pre-locked state and then closed to thefinal-locked state the coating of that part of the overlap area of thebody and cap that was not overlapped by the cap in the pre-locked statewill then become covered by the cap. The presence of that part of thecoating which is then enclosed in the final-locked state between thebody and the cap is sufficient for the hard-shell capsule to be tightlysealed. This was by no means to be foreseen.

If the cap overlaps the total overlapping area of the body, thehard-shell capsule is finally closed or in the final-locked state.Preferably, in the presence of a locking mechanism, like matchingencircling notches and/or dimples in body and cap, the finally closedcapsule may be called final-locked.

Usually dimples are preferred for the fixing the body and the cap in thepre-locked state. As a non-binding rule the matching area of dimples issmaller than the matching area of encircling notches. Thus snapped-indimples may be snapped-out again by applying less forces than those thatwould be necessary to snap-out a snapped-in fixation by matchingencircling notches.

The dimples of the body and cap are located in the area where the capcan be slid over the body matching to each other in the pre-locked stateby a snap in or snap into-place mechanism. There may be for example 2,4, or preferably 8 notches or dimples located distributed circulararound the cap.

Usually the dimples of the cap and the encircling notches of the bodyare in the area where the cap can be slid over the body, matching toeach other so that they allow the capsule to be closed by asnap-into-place mechanism in the pre-locked state. In the pre-lockedstate, the hard-shell capsule can be re-opened manually or by a machinewithout damaging, because the forces needed to open are comparativelylow. So, the “pre-locked state” is sometimes designated also as “looselycapped”.

Usually the encircling notches or matching locking rings of the body andthe cap are in the area where the cap can be slid over the body,matching to each other so that they allow the capsule to be closed by asnap-into-place mechanism in the final-locked state. In the final-lockedstate, the hard-shell capsule cannot or can be only hardly be re-openedmanually or by a machine without damaging, because the forces needed toopen are comparatively high.

Usually the dimples and the encircling notches are formed in the capsulebody or capsule cap. When the capsule parts provided with theseelevations and indentations are fitted into one another, ideally defineduniform gaps of from 10 microns to 150 microns, more particularly 20microns to 100 microns, are formed along the contact surface between thecapsule body and the capsule cap placed thereon.

Preferably, the body of the hard-shell capsule comprises a tapered rim.The tapered rim prevents the rims of the body and the cap to collide andbecoming damaged when the capsule is closed manually or by a machine.

In contrast to a hard-shell capsule, a soft-shell capsule is a weldedone-piece encapsulation capsule. A soft gel capsule is often made fromblow molded soft gelling substances and is usually filled with liquidscomprising a biologically active ingredient by injection. The inventionis not concerned with welded soft-shell one-piece encapsulationcapsules.

Sizes of Hard-Shell Capsules

The polymer coated hard-shell capsule may be derived from an uncoatedhard-shell capsule of the standard size 000, 00, 0, 1, 2, 3, 4, 5 or 9.

A closed, final-locked hard-shell capsule may have a total length in therange from about 5 to 40 mm. The diameter of the cap may be in the rangefrom about 4 to 12 mm. The diameter of the body may be in the range fromabout 2 to 11 mm. The length of the cap may be in the range from about 4to 20 mm and that of the body in the range from 8 to 30 mm. The fillvolume may be about from 0.1 to 2 ml. The difference between thepre-locked length and the final-locked length may be about 1 to 5 mm.

Capsules can be divided into standardized sizes for example from sizes000 to 5. A closed capsule of size 000 has, for example, a total lengthof about 28 mm with an outer diameter of the cap of about 9.9 mm and anouter diameter of the body of about 9.5 mm. The length of the cap isabout 14 mm, that of the body about 22 mm. The fill volume is about 1.4ml.

A closed capsule of size 5 has, for example, a total length of about 10mm and an outer diameter of the cap of about 4.8 mm and an outerdiameter of the body of about 4.6 mm. The length of the cap is about 5.6mm, that of the body about 9.4 mm. The fil volume is about 0.13 ml.

A size 0 capsule may show a length of about 23 to 24 mm in thepre-locked state and of about 20.5 to 21.5 mm in the final-locked state.Thus, the difference between the pre-locked length and the final-lockedlength may be about 2 to 3 mm.

Material of the Body and the Cap

The material of the body and the cap comprises an ethyl-, methyl- orpropyl-ether of cellulose, starch or pullulan. Cellulose ethers arederivates of cellulose in which the hydrogen atoms of the hydroxylgroups are partially or fully substituted by alkyl groups, such asethyl-, methyl- or propyl-groups. These derivates of cellulose are wellknown to a skilled person in pharmacy and galenic. Suitable materialsare methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose(HEC), hydroxypropyl cellulose (HPC) and/or hydroxypropyl methylcellulose (HPMC). Preferred is hydroxypropyl methyl cellulose (HPMC).

Coating Layer

The hard-shell capsule is provided in the pre-locked state andspray-coated with a coating solution, suspension or dispersion to createthe corresponding coating layer which covers the outer surface of thehard-shell capsule in the pre-locked state.

The coating layer may be a single layer or may comprise or consist oftwo or more Individual layers.

The hard-shell capsule is coated with a coating layer that covers thehard-shell capsule in the pre-locked state. The coating layer iscomprising one or more (meth)acrylate copolymer(s), preferably with aglass transition temperature T_(gm) of 125° C. or less (determined byDifferential Scanning Calorimetry (DSC) according to ISO11357-2:2013-05), wherein the coating layer is present in an amount ofabout 1 to 5.8, preferably 2 to 5 mg/cm², wherein a dried filmcorresponding to the composition of the coating layer shows anelongation at break of about 15 to 500%. The elongation at break isdetermined with a test sample (sample type 1B, 20 mm/min) according toDIN EN ISO 527-3:2018, February 2019.

The coating layer, which may be a single layer or may comprise orconsist of two or more individual layers, may comprise in total 10 to100, 20 to 95, 30 to 90% by weight of one or more (meth)acrylatecopolymer(s).

The coating layer, which may be a single layer or may comprise orconsist of two or more individual layers, may comprise in total 90 to 0,80 to 5, 70 to 10% by weight of pharmaceutical or nutraceuticalexcipients.

The one or more (meth)acrylate copolymer(s) and the pharmaceutical ornutraceutical excipients may add up to 100%.

“Duo Coat”

The coating layer may be a single coating layer or may comprise one ortwo or more individual layers.

An advantageous system comprising a coating layer comprising twoindividual coatings may comprise an inner coating which comprises apartially neutralized anionic (meth)acrylate copolymer or a watersoluble neutral polymer in combination with an outer coating comprisingan anionic (meth)acrylate copolymer, which is less neutralized than thematerial of the inner coating or not neutralized at all (s. WO2008/135090A1).

Glass Transition Temperature T_(gm)

Methacrylic acid-methyl methacrylate copolymers such as EUDRAGIT® L 100or EUDRAGIT® S 100 show glass transition temperatures T_(gm) of about orsomewhat above 150° C. for the EUDRAGIT® L 100 polymer or about orsomewhat above 160° C. for the EUDRAGIT® S 100 polymer, which iscomparatively high. It should be noted that the T_(gm) of EUDRAGIT® L100 or EUDRAGIT® S 100 cannot exactly be determined because of thestarting decomposition of their functional groups at 150° C. Therequired elasticity (elongation at break) of the coating layer may berealized by addition of comparatively high amounts of plasticizersand/or emulsifiers and/or detacking agents.

The inventors have found that in a preferred embodiment, a coating layermay comprise one or more (meth)acrylate copolymer(s) with a glasstransition temperature T_(gm) of 125° C. or less, preferably from minus10 to plus 115° C. These polymers are less brittle and more flexiblewhich supports the coating layer to resist against the high mechanicalforces occurring during the processing in a capsule filling machine. Incombination with these polymers, the required elasticity (elongation atbreak) of the coating layer may be realized with the addition of lessamounts of plasticizers and/or emulsifiers and/or detacking agents. Inthis embodiment methacrylic acid-methyl methacrylate copolymers may begenerally excluded.

Thus, the coating layer may comprise one or more (meth)acrylatecopolymer(s) with a glass transition temperature T_(gm) of 125° C. orless, preferably from −10 to 115° C.

Thus, the coating layer may comprise one or more (meth)acrylatecopolymer(s) with a glass transition temperature T_(gm) of 125° C. orless, preferably from −10 to 115°, wherein copolymers consisting ofpolymerized units of methacrylic acid and methyl methacrylate areexcluded.

The glass transition temperature T_(gm) is determined by DifferentialScanning Calorimetry (DSC) according to ISO 11357-2:2013-05. Thedetermination is performed with a heating rate of 20 k/min. The glasstransition temperature T_(gm) was determined by half step height methodas described in section 10.12 of DIN EN ISO 11357-2.

Thickness of the Coating Layer

The coating layer is present in an amount of about 1 to 5.8, preferably2 to 5 mg/cm².

The thickness of the coating layer may be determined by calculation ofthe amount of the coating material applied to the empty pre-lockedcapsules, for Instance in a spray coating process, in relation to thesurface area of the empty pre-locked capsules (see also examples 8 and9, FIG. 1 /1). The coating layer may be a single layer or may compriseor consist of two or more individual layers. In the case of two or moreindividual layers, the thickness of the individual layers cumulating tothe thickness of the coating layer in total.

Elongation at Break

The inventors have found that processing in a capsule filling machinerequires a certain elasticity of the coating layer. The elasticity ofthe coating layer may be characterized in that a dried filmcorresponding to the composition of the coating layer shows anelongation at break of about 15 to 500, preferably 20 to 250%.

Elongation at break may be determined according to DIN EN ISO 527-1:2012-06 (General principles, especially chapter 8) and 527-3:2018,February 2019, determination of tensile properties for films and sheetswith a thickness below 1,000 μm. The elongation at break is thepercentage increase in length that a material will achieve beforebreaking. This figure is shown as the percentage. Suspension of thecompositions for the coating layer are spread on a glass plate and driedto a film of 250 μm thickness. The elongation at break is determinedwith a test sample (sample type 1B, 20 mm/min) according to DIN EN ISO527-3:2018, February 2019.

Example for the Preparation and Testing of Polymer Films:

Formulation:

Polymer dispersion 30 g=9 g solids, used for a 250 μm film after drying.

Equipment:

Glass plate 20 cm×20 cm with a surrounding of 1 cm glass strips of0.5-0.7 cm height, resulting in a free preparation area of 381 cm. Thisglass plate is in addition covered with a self-adhesivePolytetrafluoroethylen foil (i.e. Tygaflor®).

Processing:

The polymer and diluent are mixed on a magnetic stirrer for 10 minutesat low speed. The polymer solution or suspension needs to be air free toavoid voids in the polymer foil. The Polytetrafluoroethylen coveredglass plate is levelled in an oven and the polymer solution ordispersion is poured into it. The mixture is dried for approximately 4days at 40° C. After drying the foils or sheets will be conditioned for16 hours at 23° C. and 50% relative humidity.

The resulting film thickness is approx. 250 μm.

The same method can be used to manufacture films of coating suspensions.In this case the coating suspension is prepared like usually (e.g. usingan ultra turrax). An aliquot amount for 9 g of total solids (includingformulation excipients) is diluted with demineralized water up to atotal amount of 100 g.

(Meth)Acrylate Copolymer(s)

The coating layer may comprise a (meth)acrylate copolymer selected fromcopolymers comprising polymerized units of methacrylic acid and ethylacrylate, of methacrylic acid and methyl methacrylate, of ethyl acrylateand methyl methacrylate or of methacrylic acid, methyl acrylate andmethyl methacrylate, from a mixture of a copolymer comprisingpolymerized units of methacrylic acid and ethyl acrylate with acopolymer comprising polymerized units of methyl methacrylate and ethylacrylate and a mixture of a copolymer comprising polymerized units ofmethacrylic acid, methyl acrylate and methyl methacrylate with acopolymer comprising polymerized units of methyl methacrylate and ethylacrylate.

The coating layer may comprise a (meth)acrylate copolymer comprisingpolymerized units of 40 to 60% by weight of methacrylic acid and 60 to40% by weight of ethyl acrylate (type EUDRAGIT® L 100-55). A suitablesecond polymer is EUDRAGIT® L 100-55 (Evonik Nutrition & Care GmbH.Darmstadt, Germany), which is a copolymer comprising polymerized unitsof 50% by weight of methacrylic acid and 50% by weight of ethylacrylate. EUDRAGIT® L 30 D-55 is a 30% by weight aqueous dispersion ofEUDRAGIT® L 100-55. The glass transition temperature T_(gm) of EUDRAGIT®L 100-55 is about 110° C.

The coating layer may comprise a (meth)acrylate copolymer comprisingpolymerized units of 5 to 15% by weight methacrylic acid, 60 to 70% byweight of methyl acrylate and 20 to 30% by weight methyl methacrylate(type EUDRAGIT® FS). A suitable copolymer is EUDRAGIT® FS which is acopolymer polymerized from 25% by weight of methyl methacrylate, 65% byweight of methyl acrylate and 10% by weight of methacrylic acid.EUDRAGIT® FS 30 D is a dispersion comprising 30% by weight EUDRAGIT® FS.The glass transition temperature T_(gm) of EUDRAGIT® FS is about 45° C.

The coating layer may comprise a (meth)acrylate copolymer comprisingpolymerized units of 60 to 80% of ethyl acrylate and 40 to 20% by weightof methyl methacrylate (type EUDRAGIT® NE or the type EUDRAGIT® NM).EUDRAGIT® NE and EUDRAGIT® NM are copolymers comprising free-radicallypolymerized units of 28 to 32% by weight of methyl methacrylate and 68to 72% by weight of ethyl acrylate. The glass transition temperatureT_(gm) of EUDRAGIT® NE is about minus 8° C.

The coating layer may comprise a (meth)acrylate copolymer comprisingpolymerized units of 40 to 60% by weight of methacrylic acid and 60 to40% by weight of methyl methacrylate (type EUDRAGIT® L 100). EUDRAGIT® L100 is a copolymer polymerized from 50% by weight of methyl methacrylateand 50% by weight of methacrylic acid. The glass transition temperatureT_(gm) of EUDRAGIT® L 100 is about or somewhat above 150° C.

The coating layer may comprise a (meth)acrylate copolymer comprisingpolymerized units of 20 to 40% by weight of methacrylic acid and 60 to80% by weight of methyl methacrylate (type EUDRAGIT® S 100). EUDRAGIT® S100 is a copolymer polymerized from 70% by weight methyl methacrylateand 30% by weight methacrylic acid. The glass transition temperatureT_(gm) of EUDRAGIT® S 100 is about or somewhat above 160° C.

Mixtures of (Meth)Acrylate Copolymers

The coating layer may comprise a mixture of (meth)acrylate copolymers ofthe above-mentioned type EUDRAGIT® L 100-55 and of type EUDRAGIT® NE ortype EUDRAGIT® NM. The glass transition temperature T_(gm) of EUDRAGIT®NE and EUDRAGIT® NM is about −8° C.

Type EUDRAGIT® NE or type EUDRAGIT® NM (meth)acrylate copolymers are(meth)acrylate copolymers comprising polymerized units of 60 to 80% ofethyl acrylate and 40 to 20% by weight of methyl methacrylate. EUDRAGIT®NE and EUDRAGIT® NM are copolymers comprising free-radically polymerizedunits of 28 to 32% by weight of methyl methacrylate and 68 to 72% byweight of ethyl acrylate. The coating layer may comprise a(meth)acrylate copolymer comprising polymerized units of 60 to 80% ofethyl acrylate and 40 to 20% by weight of methyl methacrylate.

Preference is given to (meth)acrylate copolymers which, according to WO01/68767, have been prepared as dispersions using 1-10% by weight of anon-ionic emulsifier having an HLB value of 15.2 to 17.3. The latteroffers the advantage that there is no phase separation with formation ofcrystal structures by the emulsifier (EUDRAGIT® NM type).

Preferably, the coating layer may comprise a mixture of a (meth)acrylatecopolymer comprising polymerized units of 40 to 60% by weight ofmethacrylic acid and 60 to 40% by weight of ethyl acrylate and a(meth)acrylate copolymer comprising polymerized units or 60 to 80% ofethyl acrylate and 40 to 20% by weight of methyl methacrylate at a ratiofrom 10:1 to 1:10 by weight.

The coating layer may comprise a mixture of a (meth)acrylate copolymerof the above-mentioned types EUDRAGIT® FS and the type EUDRAGIT® L100-55.

Preferably, the coating layer may comprise a mixture of a (meth)acrylatecopolymer comprising polymerized units of 5 to 15% by weight methacrylicacid, 60 to 70% by weight of methyl acrylate and 20 to 30% by weightmethyl methacrylate and a (meth)acrylate copolymer comprisingpolymerized units of 40 to 60% by weight of methacrylic acid and 60 to40% by weight of ethyl acrylate at a ratio from 1:1 to 5:1 by weight.

The coating layer may also comprise a mixture of a (meth)acrylatecopolymer(s) in the form of a core-shell polymer from two (meth)acrylatecopolymer(s). The coating layer may comprise a (meth)acrylate copolymerwhich is a core-shell polymer, comprising 50 to 90, preferably 70 to 80%by weight of a core, comprising polymerized units of 60 to 80,preferably 65 to 75% by weight of ethyl acrylate and 40 to 20,preferably 35 to 25% by weight of methyl methacrylate, and 50 to 10,preferably 30 to 20% by weight of a shell, comprising polymerized unitsof 40 to 60, preferably 45 to 55% by weight of ethyl acrylate and 80 to40, preferably 55 to 45% by weight of methacrylic acid.

A suitable core-shell polymer is EUDRAGIT® FL 30 D-55 (Evonik Nutrition& Care GmbH, Darmstadt, Germany), which is a commercially available 30%by weight aqueous dispersion of a copolymer from a two-stage emulsionpolymerization process, with a core of about 75% by weight, comprisingpolymerized units of about 70% by weight of ethyl acrylate and 30% byweight of methyl methacrylate, and a shell of about 25% by weight,comprising polymerized units of 50% by weight ethyl acrylate and 50% byweight methacrylic acid. The glass transition temperature T_(gm) of thepolymer of EUDRAGIT® FL 30D-55 is about 8° C.

Pharmaceutical or nutraceutical excipients Pharmaceutical ornutraceutical excipients are well known to a skilled person and oftenformulated along with the biologically active Ingredient contained inthe coated hard-shell capsule and/or with the polymer coating of thehard-shell capsule as disclosed and claimed herein. All pharmaceuticalor nutraceutical excipients used must be toxicologically safe to be usedin pharmaceuticals or nutraceuticals without risk for patients orconsumers.

Pharmaceutically or nutraceutically acceptable excipients, may beselected from the group of antioxidants, brighteners, binding agents,flavouring agents, flow aids, fragrances, glidants,penetration-promoting agents, pigments, plasticizers, polysaccharidepolymers, emulsifiers, pore-forming agents or stabilizers orcombinations thereof. A pharmaceutically or nutraceutically acceptableexcipient is an excipient, which is allowed to be used for theapplication in the pharmaceutical or nutraceutical field.

The pharmaceutical or nutraceutical excipients may preferably compriseone or more plasticizers and/or one or more detacking agents.

The addition of plasticizer(s) to the (meth)acrylate copolymer(s) isusually lowering the glass transition temperature of the mixture,elongation at break is usually Increased. The effect may depend on thetype and amount of plasticizer that is added. Plasticizer(s) may beselected from the groups of alkyl citrates, glycerol esters, alkylphthalates, alkyl sebacates, sucrose esters, sorbitan esters, glycerol,propylene glycol and polyethylene glycols. Preferred plasticizers aretriethyl citrate, polyethylene glycol 20,000 and propylene glycol. Theamount of plasticizer added may be in the range of 2 to 50, preferably 5to 30% by weight calculated on the weight of the (meth)acrylatecopolymer(s).

The addition of detacking agents to the (meth)acrylate copolymer(s) isusually decreasing the tackiness of the mixture respectively of thecoated film. Detacking agent(s) may be selected from Ca-stearate orMg-stearate, glycerol monostearate and talc. The amount of detackingagent added may be in the range of 2 to 60, preferably 5 to 55% byweight calculated on the weight of the (meth)acrylate copolymer(s).

The coating layer may further comprise an emulsifier, preferablypolysorbate 80. The amount of emulsifier added may be in the range of 1to 30, preferably 3 to 25% by weight calculated on the weight of the(meth)acrylate copolymer(s).

Top Coat

The coating layer may comprise or include an additional top coat in anamount of 0.2 to 0.8 mg/cm², comprising hydroxypropyl methyl celluloseand optionally pigments or colorants. The top coat may also comprisefurther excipient polymers such as polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) or Opadry®. Preferably the top coat does notcomprise essential amounts or no (meth)acrylate copolymer(s) at an.

Colon Delivery Combination

Especially for colon delivery, preference is given to the addition of anexcipient polymer, which Is polysaccharide polymer selected from thegroup consisting of starch, amylose, amylopectin, chitosan, chondroitinsulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan,chitin, curdulan and levan in coating layer comprising one or more(meth)acrylate copolymer(s) with a pH threshold at pH 5 or above (s. EP2018159B1). The ratio of the polysaccharide polymer to the one or more(meth)acrylate copolymer(s) may be up to 50:50, preferably up to 35:65.(Meth)acrylate copolymers with a pH threshold at pH 5 are preferably ofthe type EUDRAGIT® L100 or EUDRAGIT® S, preferably used in combinationwith a starch comprising at least 35% by weight amylose. The pHthreshold is the pH below which the one or more (meth)acrylatecopolymer(s) are Insoluble and at or above they are soluble in buffer,intestinal juice or simulated intestinal fluid.

Capsule Filling Machine

The polymer-coated hard-shell capsule is provided in the pre-lockedstate to a capsule-filling machine, which performs the steps ofseparating the body and the cap, filling the body with the fill andrejoining the body and the cap in the final-locked state.

The capsule filling machine used may be a capsule filling machine,preferably a fully automated capsule filling machine, that is capable toproduce filled and closed capsules at a speed with an output of 1.000 ormore filled and finally closed capsules per hour. Capsule fillingmachines, preferably fully automated capsule filling machines, are wellknown in the art and commercially available from several companies. Asuitable capsule filling machine as used in the examples may be forinstance ACG, model AFT Lab.

The capsule filling machine used may be preferably operated at a speedwith an output of 1,000 or more, preferably 10,000 or more, 100,000 ormore, 10,000 up to 500,000, filled and finally closed capsules per hour.

Capsule Filling Machine General Operations

Before the capsule filling process, the capsule filling machine isprovided with a sufficient number or amount of pre-coated hard-shellcapsules in the pre-locked state. The capsule filling machine is alsoprovided with sufficient amounts of fill to be filled in duringoperation.

The hard-shell capsules in the pre-locked state may fall by gravity intofeeding tubes or chutes. The capsules may be uniformly aligned bymechanically gauging the diameter differences between the cap and thebody. The hard-shell capsules are then usually fed, in properorientation, into a two-section housing or brushing.

The diameter of the upper bushing or housing is usually larger than thediameter of the capsule body bushing; thus, the capsule cap may beretained within an upper bushing while the body Is pulled into a lowerbushing by vacuum. Once the capsule is opened/the body and the cap areseparated, the upper and lower housing or bushing are separated toposition the capsule body for filling.

The open capsule body is then filled with the fill. Various types offilling mechanisms may be applied, with respect to the differentfillings such as granules, powders, pellets or mini-tablets. Capsulefilling machines in general employ a variety of mechanisms to handle thevarious dosage ingredients as well as various numbers of fillingstations. The dosing systems are usually based on volumetric or amountsof fills governed by the capsule size and capacity of the capsule body.The empty capsule manufacturers usually provide reference tables thatIndicate the volume capacity of their capsule body and the maximum fillweight for different capsule sizes based on the density of the fillmaterial. After the filling, the body and the cap are rejoined by themachine in the final-locked state or position.

EXAMPLES

Elongation at break values of dried films corresponding to thecomposition of the coating layer of examples 1 to 7.

Elongation at break may be determined according to DIN EN ISO527-3:2019-02, determination of tensile properties for plastic foils andsheets with a thickness below 1.000 μm. The elongation at break is thepercentage Increase in length that a material will achieve beforebreaking. This figure is shown as the percentage. Suspension of thecompositions for the coating layer are spread on a glass plate and driedto a film of 250 μm thickness. The elongation at break is determinedwith these samples according to DIN EN ISO 527-3:2019-02.

Example for the Preparation and Testing of Polymer Films:

Formulation:

Polymer dispersion 30 g=9 g solids, used for a 250 μm film after drying.

Equipment:

Glass plate 20 cm×20 cm with a surrounding of 1 cm glass strips of0.5-0.7 cm height, resulting in a free preparation area of 361 cm². Thisglass plate is in addition covered with a self-adhesivePolytetrafluoroethylen foil (i.e. Tygaflor®).

Processing:

The polymer and diluent are mixed on a magnetic stirrer for 10 minutesat low speed. The polymer solution or suspension needs to be air free toavoid voids in the polymer foil. The Polytetrafluoroethylen coveredglass plate is levelled in an oven and the polymer solution ordispersion is poured into it. The mixture is dried for approximately 4days at 40° C. After drying the foils or sheets will be conditioned for16 hours at 23° C. and 50% relative humidity.

The resulting film thickness is approx. 250 μm.

The same method can be used to manufacture films or coating suspensions.In this case the coating suspension is prepared like usually (e.g. usingan ultra turrax). An aliquot amount for 9 g of total solids (includingformulation excipients) is diluted with demineralized water up to atotal amount of 100 g.

Results

Coating Elongation layer at break Example [mg/cm2] [%] Process 1Inventive 3.6 ca. 70 Pre-coated capsules, capsule filling machine 2Comparative 3.6 ca. 70 Uncoated capsules, capsule filling machine,post-coating 3 Comparative 6.0 ca. 70 Pre-coated capsules, capsulefilling machine 4 Inventive 3.3 ca. 30 Pre-coated capsules, capsulefilling machine 5 Comparative 3.3 ca. 30 Uncoated capsules, capsulefilling machine, post-coating 6 Inventive 2.9 ca. 70 Pre-coatedcapsules, capsule filling machine 7 Comparative 2.8 ca. 5  Pre-coatedcapsules, capsule filling machine

Example 1 (Inventive)—Enteric Coating of EUDRAGIT® L 30D-55 andEUDRAGIT® NM 30D Combination on Pre-Locked Capsules in Drum Coater andAutomatic Capsule Filling

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The capsules were coated in the pre-lockedstate utilizing a drum coater.

TABLE 1 Formulation Example 1 - Coating on Kcaps ® HPMC Size 0 capsules(Batch size 90 g i.e. 833 capsules) Solid Composition MaterialComposition Percentage EUDRAGIT ® L 30 D-55 2.7 mg/cm² 75.0% EUDRAGIT ®NM 30D 0.3 mg/cm² 8.33% Triethyl citrate 20% on ds* 16.67% Demineralizedwater On demand n/a Solid content 10% w/w Total solid weight gain 3.6mg/cm² *Quantity based on dry polymer substance [% j

TABLE 2 Process Parameter Example 1 Parameter Value Machine Neocota 5DBatch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat patternpressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.]50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 33-38 Exhaustair temperature [° C.] 28-31 Product temperature [° C.] 28-29 Spray rate[g/min/kg]  8-16 Process time [min] 190  

Encapsulation Parameter

557 mg of Omeprazole pellets (5% Omeprazole) were filled into thepolymer coated pre-locked capsules using an automatic Capsule fillingequipment AFTLAB, ACG with a pellets filling set up using standardformat size 0 tooling for capsule opening, transport, filling andclosing. The machine output was set to 5,000-5,400 cps/hour.

Capsules tested in automatic capsule filling machine, 3.0 mg/cm² polymeror 3.6 mg/cm² total solid weight gain feasible to process automatically.Capsule filling operation was smooth, capsules body and caps were easilyopened and fit into the machine parts. Yield of 98% could be achieved(only 2% capsules were rejected by machine) on automatic capsule fillingmachine.

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL for 2 hours

Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

Paddle speed: 100 rpm

TABLE 3 Dissolution Results (n = 12) Example 1 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 2.8 1.8 pH 6.8 135 27.5 9.4pH 6.8 150 89.0 10.2 pH 6.8 165 97.0 2.0 pH 6.8 180 95.7 1.5

Example 2 (Comparative)—Enteric Coating of EUDRAGIT® L 30D-55 andEUDRAGIT® NM 30D Combination on Filled and Locked Capsules (OmeprazolePellets) in Drum Coater

Encapsulation Parameter

590 mg of Omeprazole pellets (5% Omeprazole) were filled into the KcapsHPMC Size 0 capsules using an automatic Capsule filling equipmentAFTLAB. ACG with a pellets filling set up using standard format size 0tooling for capsule opening, transport, filling and closing. The machineoutput was set to 5,000-5,400 cps/hour.

Capsule filling operation was smooth, capsules body and caps were easilyopened and fit Into the machine parts. Yield of 99.7% could be achieved(only 0.3% capsules were rejected by machine) on automatic capsulefilling machine.

Enteric Coating on Omeprazole Flied Capsules:

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The omeprazole filled capsules were thencoated in the locked state utilizing a drum coater.

TABLE 4 Formulation Example 2- Coating on Omeprazole filled Kcaps ® HPMCSize 0 capsules (Batch size 550 g i.e 833 capsules) Solid CompositionMaterial Composition Percentage EUDRAGIT ® L 30 D-55 2.7 mg/cm² 75.0%EUDRAGIT ® NM 30D 0.3 mg/cm² 8.33% Triethyl citrate 20% on ds* 16.67%Demineralized water On demand n/a Solid content 10% w/w Total solidweight gain 3.6 mg/cm² *Quantity based on dry polymer substance [%]

TABLE 5 Process Parameter Example 2 Parameter Value Machine Neocota 5DBatch size [g] 550    Nozzle bore [mm] 0.8 Internal tube diameter [mm]3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat patternpressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.]50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 35-38 Exhaustair temperature [° C.] 29-30 Product temperature [° C.] 28-29 Spray rate[g/min/kg] 1.36-2.72 Process time [min] 120   

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP 11) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL

Paddle speed: 100 rpm

TABLE 6 Dissolution Results (n = 12) Example 1 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 25.8 20.4

Dissolution testing of Example-2 was only carried out in the 0.1N HClfor 2 hours because Acid release/degradation of Omeprazole observedafter 2 hours exposure to 0.1N HCl. At same coating build up entericpolymer coating on filled and locked capsules failed to give acidresistance as compared to coating on Pre-locked capsules followed byfilling (Example-1).

Example 3 (Comparative)—Enteric Coating of EUDRAGIT® L 30D-55 andEUDRAGIT® NM 30D Combination on p-Locked Capsules in Drum Coater andAutomatic Capsule Filling

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The capsules were coated in the pre-lockedstate utilizing a drum coater.

TABLE 7 Formulation Example 3- Coating on Kcaps ® HPMC Size 0 capsules(Batch size 90 g i.e. 833 capsules) Solid Composition MaterialComposition Percentage EUDRAGIT ® L 30 D-55 4.5 mg/cm² 75.0% EUDRAGIT ®NM 30D 0.5 mg/cm² 8.33% Triethyl citrate 20% on ds* 16.67% Demineralizedwater On demand n/a Solid content 10% w/w Total solid weight gain   6mg/cm² *Quantity based on dry polymer substance [%]

TABLE 8 Process Parameter Example 3 Parameter Value Machine Neocota 5DBatch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat patternpressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.]50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 32-38 Exhaustair temperature [° C.] 28-32 Product temperature [° C.] 28-30 Spray rate[g/min/kg]  8-16 Process time [min] 375   

Encapsulation Parameter

595 mg of Omeprazole pellets (5% Omeprazole) was filled into the polymercoated pre-locked capsules using an automatic Capsule filling equipmentAFTLAB, ACG with a pellets filling set up using standard format size 0tooling for capsule opening, transport, filling and closing. The machineoutput was set to 1,000-1,200 cps/hour.

Capsules tested in automatic capsule filling machine. At 5.0 mg/cm²polymer or 6.0 mg/cm² total solid weight gain the limitation was thestandard tooling which was not able to operate with the pre-lockedcapsules due to the increased layer thickness. Capsule filling operationwas not smooth, capsules body and caps were easily opened but failed tofit into the machine parts due to increase in the coating thickness.Yield of only 67% could be achieved and 33% capsules were rejected bythe machine. Due to high rejection rate the filed capsules were notanalyzed for dissolution testing.

Example 4 (Inventive)—Enteric Coating of EUDRAGIT® FS 30D and EUDRAGIT®L 30-65 Combination on p-Locked Capsules in Drum Coater and AutomaticCapsule Filling

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added Into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The capsules were coated in the pre-lockedstate utilizing a drum coater.

TABLE 9 Formulation Example 4 - Coating on Kcaps ® HPMC Size 0 capsules(Batch size 90 g i.e. 833 capsules) Solid Composition MaterialComposition Percentage EUDRAGIT ® FS 300 2.25 mg/cm² 68.18% EUDRAGIT ® L30 D-55 0.75 mg/cm² 22.73% Triethyl citrate 10% on ds* 9.09%Demineralized water On demand n/a Solid content 10% w/w Total solidweight gain  3.3 mg/cm² *Quantity based on dry polymer substance [%]

TABLE 10 Process Parameter Example 4 Parameter Value Machine Neocota 5DBatch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat patternpressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.]50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 36-38 Exhaustair temperature [° C.] 28-29 Product temperature [° C.] 28-29 Spray rate[g/min/kg] 8   Process time [min] 240   

Encapsulation Parameter

525 mg of Metoprolol pellets (40% Metoprolol) were filled into thepolymer coated pre-locked capsules using an automatic Capsule fillingequipment AFTLAB, ACG with a pellets filling set up using standardformat size 0 tooling for capsule opening, transport, filling andclosing. The machine output was set to 5,000-5,400 cps/hour.

Capsules tested in automatic capsule filling machine, 3.0 mg/cm² polymeror 3.3 mg/cm² total solid weight gain feasible to process automatically.Capsule filling operation was smooth, capsules body and caps were easilyopened and fit into the machine parts. Yield or 97% could be achieved(only 3% capsules were rejected by machine) on automatic capsule fillingmachine.

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL for 2 hours

Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

Media III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

Paddle speed: 100 (media1)/100 (media2)/50 (media3)

TABLE 11 Dissolution Results (n = 12) Example 4 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.00 0.00 0.1N HCL 120 0.18 0.34 pH 6.8 18014.56 19.77 pH 7.4 195 34.89 20.80 pH 7.4 210 54.54 15.56 pH 7.4 22571.56 9.94 pH 7.4 240 83.58 7.44 pH 7.4 270 90.44 6.71 pH 7.4 300 91.307.84

Example 5 (Comparative)—Enteric Coating of EUDRAGIT® FS 30D andEUDRAGIT® L 30D-55 Combination on Filled and Locked Capsules (MetoprololPellets) in Drum Coater

Encapsulation Parameter

517 mg of Metoprolol pellets (40% Metoprolol) were filled Into the KcapsHPMC Size 0 capsules using an automatic Capsule filling equipmentAFTLAB. ACG with a pellets filling set up using standard format size 0tooling for capsule opening, transport, filling and closing. The machineoutput was set to 5,000-5,400 cps/hour.

Capsule filling operation was smooth, capsules body and caps were easilyopened and fit Into the machine parts. Yield of 100% could be achievedon automatic capsule filling machine.

Enteric Coating on Metoprolol Filled Capsules:

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The Metoprolol filled capsules were thencoated in the locked state utilizing a drum coater.

TABLE 12 Formulation Example 5- Coaling on Metoprolol filled Kcaps ®HPMC Size 0 capsules (Batch size 550 g i.e 833 capsules) SolidComposition Material Composition Percentage EUDRAGIT ® FS 30D 2.25mg/cm² 58.18% EUDRAGIT ® L 30 D-55 0.75 mg/cm² 22.73% Triethyl citrate10% on ds* 9.09% Demineralized water On demand n/a Solid content 10% w/wTotal solid weight gain  3.3 mg/cm² *Quantity based on dry polymersubstance [%]

TABLE 13 Process Parameter Example 5 Parameter Value Machine Neocota 5DBatch size [g] 550    Nozzle bore [mm] 0.8 Internal tube diameter [mm]3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat patternpressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.]50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 36-38 Exhaustair temperature [° C.] 28-30 Product temperature [° C.] 28-29 Spray rate[g/min/kg] 1.36-2.72 Process time [min] 140   

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL for 2 hours

Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

Media III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

Paddle speed: 100 (media1)/100 (media2)/50 (media3)

TABLE 14 Dissolution Results (n = 12) Example 5 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 27.3 40.6 pH 6.8 180 84.916.0

Dissolution testing of Example-5 was only carried out in the 0.1N HClfor 2 hours and pH 6.8 buffer for 1 hour because complete release ofMetoprolol observed in pH 6.8 buffer. At same coating build up entericpolymer coating on filled and locked capsules failed to give acidresistance as compared to coating on Pre-locked capsules followed byfilling (Example-4).

Example 6 (Inventive)—Enteric Coating of EUDRAGIT® L 30D-55 andEUDRAGIT® NM 30D Combination on Pre-Locked Capsules Followed by Top Coatof HPMC in Drum Coater and Automatic Capsule Filling

The EUDRAGIT® polymer(s) were mixed in a suitable sized container. Theadditional excipients were added into the water while gently stirring.After a suitable post stirring time the excipient suspension was addedto the polymer dispersion. The spraying suspension was gently stirredduring the coating process. The capsules were coated in the pre-lockedstate utilizing a drum oater. Top coat: HPMC was dissolved in waterunder stirring and sprayed on to the coated capsules utilizing a drumcoater.

TABLE 15 Formulation Example 6- Coaling on Kcaps ® HPMC Size 0 capsules(Batch size 500 g i.e. 4595 capsules) Solid Composition Coating MaterialComposition Percentage Functional coat EUDRAGIT ® L 30 D-55 1.8 mg/cm²75.0% EUDRAGIT ® NM 30D 0.2 mg/cm² 8.33% Triethyl citrate 20% on ds*16.67% Demineralized water On demand n/a Solid content 10% w/w Totalsolid weight gain 2.4 mg/cm² Top coat HPMC 3cps 0.5 mg/cm² 100%Demineralized water On demand n/a Solid content 5% w/w Total solidweight gain 0.5 mg/cm² *Quantity based on dry polymer substance [%]

TABLE 16 Process Parameter Example 6 Value Value Functional coat Topcoat Parameter (EUDRAGIT ®) (HPMC) Machine Neocota 5D Neocota 5D Batchsize [g] 500    559    Nozzle bore [mm] 0.8 0.8 Internal tube diameter[mm] 3.0 3.0 Peristaltic pump Flowtech Flowtech Atomizing pressure [bar]1.5 1.5 Flat pattern pressure [bar] 1.0 1.0 Room temperature [° C.]21-24 21-24 Room humidity [% r.h.] 50-55 50-55 Pan speed [rpm] 8   8  Inlet air temperature [° C.] 50-58 38-40 Exhaust air temperature 28-3129-31 [° C.] Product temperature [° C.] 27-29 28-29 Spray rate[g/min/kg] 4.5-18  6.70-10.7 Process time [min] 105    60  

Encapsulation Parameter

590 mg of Omeprazole pellets (5% Omeprazole) were filled into thepolymer coated pre-locked capsules using an automatic Capsule fillingequipment AFTLAB, ACG with a pellets filling set up using standardformat size 0 tooling for capsule opening, transport, filling andclosing. The machine output was set to 5,000-5,400 cps/hour.

Capsules tested in automatic capsule filling machine, 2.5 (2.0EUDRAGIT+0.5 HPMC) mg/cm polymer or 2.9 (2.4 EUDRAGIT+0.5 HPMC) mg/cm²solid weight gain feasible to process automatically. Capsule fillingoperation was smooth, capsules body and caps were easily opened and fitinto the machine parts. Yield of 95% could be achieved (only 5% capsuleswere rejected by machine) on automatic capsule filling machine.

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL for 2 hours

Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

Paddle speed: 100 rpm

TABLE 17 Dissolution Results (n = 6) Example 1 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 1.7 0.6 pH 6.8 135 43.710.8 pH 6.8 150 91.6 7.1 pH 6.8 165 94.4 1.4 pH 6.8 180 93.3 1.3

Comparative Example 7—Enteric Coating of Standard EUDRAGIT® L 30D-55Coating with Glycerol Mono Stearate (GMS) on Pre-Locked CapsulesFollowed by Top Coat of HPMC in Drum Coater and Automatic CapsuleFilling

GMS emulsion was prepared by adding Polysorbate 80 (33% solution),Triethyl citrate and GMS in hot ater (70-80° C.) under high shearhomogenizer for 10 minutes. Prepared GMS emulsion was allowed to cooldown at room temperature and then added to EUDRAGIT® polymer dispersionunder overhead stirring. The spraying suspension was gently stirredduring the coating process. The capsules were coated in the pre-lockedstate utilizing a drum coater. Top coat: HPMC was dissolved in waterunder stirring and sprayed on to the coated capsules utilizing a drumcoater.

TABLE 18 Formulation Example 7- Coaling on Kcaps ® HPMC Size 0 capsules(Batch size 90 g i.e. 833 capsules) Solid Composition Coating MaterialComposition Percentage Functional coat EUDRAGIT ® L   2 mg/cm² 85.47% 30D-55 Polysorbate 80 2% on ds* 1.71% (33% solution) Triethyl citrate 10%on ds* 8.55% Glycerol mono stearate 5% on ds* 4.27% Demineralized waterOn demand n/a Solid content 10% w/w Total solid 2.34 mg/cm²  weight gainTop coat HPMC 3cps 0.5 mg/cm² 100% Demineralized water On demand n/aSolid content 5% w/w Total solid 0.5 mg/cm² weight gain *Quantity basedon dry polymer substance [%]

TABLE 19 Process Parameter Example 7 Value Value Functional coat Topcoat Parameter (EUDRAGIT ®) (HPMC) Machine Neocota 5D Neocota 5D Batchsize [g] 90   100    Nozzle bore [mm] 0.8 0.8 Internal tube diameter[mm] 3.0 3.0 Peristaltic pump Flowtech Flowtech Atomizing pressure [bar]1.5 1.5 Flat pattern pressure [bar] 0.5 0.5 Room temperature [° C.]21-24 21-24 Room humidity [% r.h.] 50-55 50-55 Pan speed [rpm] 11   11  Inlet air temperature [° C.] 34-36 36-37 Exhaust air temperature 27-3130-31 [° C.] Product temperature [° C.] 27-29 28-29 Spray rate[g/min/kg]  8.33-16.66  8.33-16.66 Process time [min] 120    30  

Encapsulation Parameter

590 mg of Omeprazole pellets (5% Omeprazole) were filed Into the polymercoated pre-locked capsules using an automatic Capsule filling equipmentAFTLAB, ACG with a pellets filling set up using standard format size 0tooling for capsule opening, transport, filling and closing. The machineoutput was set to 5,000-5,400 cps/hour.

Capsules tested in automatic capsule filling machine, 2.5 (2.0EUDRAGIT+0.5 HPMC) mg/cm² polymer or 2.85 (2.35 EUDRAGIT+0.5 HPMC)mg/cm² solid weight gain feasible to process automatically. Capsulefilling operation was smooth, capsules body and caps were easily openedand fit into the machine parts. Yield of 98.36% could be achieved (only1.6% capsules were rejected by machine) on automatic capsule fillingmachine.

Dissolution Test

Method:

Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

Detection method: HPLC analysis

Temperature: 37.5° C.

Media I: 500 ml 0.1 N HCL for 2 hours

Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

Paddle speed: 100 rpm

TABLE 20 Dissolution Results (n = 6) Example 1 Time Mean Media [min] [%released] SD 0.1N HCL 0 0.00 0.00 0.1N HCL 120 11.02 3.16 pH 6.8 13543.63 17.04 pH 6.8 150 86.71 11.45 pH 6.8 165 90.61 14.95 pH 6.8 18094.22 7.95

Example 8—Determination of Capsule Overlap

Dimensions and tolerances of different commercially available capsuleswith respect to mean difference between pre-locked and locked lengths.

TABLE 21 Hard-shell Capsule Dimensions (1/2) Capsugel Capsugel CapsugelManufacturer Transparent White Transparent Color #0 Vcaps ® plus #0Vcaps ® plus #1 Vcaps ® plus Size Un- pre- Final- Un- pre- Final Un-pre- Final Locking stage locked locked Locked locked locked Lockedlocked locked Locked Length [mm] 29.16 23.65 21.38 29.16 23.76 20.9126.39 21.19 19.03 SD [mm] 0.19 0.2 0.16 0.17 0.15 0.07 Minimum [mm]23.25 21 23.43 20.67 20.95 18.9 Maximum 23.95 21.7 23.99 21.31 21.419.15 [mm] Overlap length 5.51 2.27 5.4 2.85 5.2 2.16 [mm] Total Overlap7.78 8.25 7.36 length [mm] Overlap level 71% 100% 65% 100% 71% 100%

TABLE 22 Hard-shell Capsule Dimensions (2/2) Capsugel ACG ACGManufacturer Transparent Transparent White Color #3 Vcaps ® plus #0Naturecaps #0EL Naturecaps Size Un- pre- Final Un- pre- Final Un- pre-Final Locking stage locked locked Locked locked locked Locked lockedlocked Locked Length [mm] 21.67 17.69 15.74 29.2 23.04 20.92 32 25.1722.87 SD [mm] 0.16 0.17 0.12 0.16 0.07 0.17 Minimum [mm] 17.39 15.2322.65 20.68 25.01 22.59 Maximum [mm] 17.94 15.98 23.21 21.22 25.29 23.1Overlap length 3.98 1.95 6.16 2.12 6.83 2.3 [mm] Total Overlap 5.93 8.289.13 [mm] Overlap level 67% 100% 74% 100% 75% 100%

Example 9—Surface Area Calculation and Colon Targeting Coating ofPre-Locked Capsules in Drum Coater

Since a certain coating layer thickness is required to achieve thedesired film functionality, the required amount of coating materialdepends on the surface area of the substrate. For this reason coatingquantities are expressed as mg of total dry substance per cm² ofsubstrate surface area.

Below the equation of pre-locked capsule surface are is describedconsidering the mean difference between the pre-locked state and theaccumulated length of the separate capsule halves, body and cap.

$A_{\frac{1}{2}{Sphere}} = {2\left( \frac{d}{2} \right)^{2}\pi}$$A_{{Cylinder},{body}} = {2{\pi\left( \frac{d}{2} \right)}\left( {h - h_{overlap}} \right)}$$A_{{Cylinder},{cap}} = {2{\pi\left( \frac{d}{2} \right)}h}$$A_{{Capsule} - {segment}} = {A_{\frac{1}{2}{sphere}} + A_{Cylinder}}$A_(Pre − lockedcapsule) = A_(Body) + A_(Cylinder)

A=Surface Area

h=Length

d=Diameter

Calculation Example 9 for the Calculation of the Outer Capsule Surfacein the Pre-Locked State

TABLE 23 Vcaps ® Plus Capsule Specifications: Size 00el 00 0el 0 1 1el 23 4 Weight Weight [mg] 130 122 107 96 76 81 61 47 38 Tolerance [mg] ±10±7 ±7 ±6 ±5 ±5 ±4 ±3 ±3 Length of the capsules halves (body and cap)Body [mm] 22.20 20.22 20.19 18.44 16.61 17.70 15.27 13.59 12.19Tolerance [mm] ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 Cap[mm] 12.95 11.74 11.68 10.72 9.78 10.49 8.94 8.08 7.21 Tolerance [mm]±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 External diameterBody [mm] 8.18 8.18 7.34 7.34 6.63 6.63 6.07 5.57 5.05 Cap [mm] 8.538.53 7.65 7.64 6.91 6.91 6.35 5.82 5.32 Overall length in thefinal-locked state Length [mm] 25.3 23.30 23.5 21.70 19.40 20.40 18.0015.90 14.30 Tolerance [mm] ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30±0.30 ±0.30

FIG. 1 /1 shows a schematic drawing of the body (left) and the cap(right) of a Vcaps® Plus size 1 hard-shell capsule with the relevantdimensions in mm. The dimensions are used in the calculation example 9for the calculation of the outer capsule surface in the pre-lockedstate. The dimensions are:

Body: length=16.61 mm, cylinder (length of the cylindrical part)=13.29mm, outer diameter=6.63 mm

Cap: length=9.78 mm, cylinder (length of the cylindrical part)=6.32 mm,outer diameter=6.91 mm

$A_{{\frac{1}{2}{Sphere}},{Body}} = {{2\left( \frac{6.63}{2} \right)^{2}\pi} = {69.05\left\lbrack {mm}^{2} \right\rbrack}}$$A_{{Cylinder},{Body}} = {{2{\pi\left( \frac{6.63}{2} \right)}\left( {13.29 - 5.2} \right)} = {168.5\left\lbrack {mm}^{2} \right\rbrack}}$$A_{{\frac{1}{2}{Sphere}},{Cap}} = {{2\left( \frac{6.91}{2} \right)^{2}\pi} = {75.\left\lbrack {mm}^{2} \right\rbrack}}$$A_{{Cylinder},{Cap}} = {{2{\pi\left( \frac{6.91}{2} \right)}6.32} = {137.2\left\lbrack {mm}^{2} \right\rbrack}}$A_(Capsule − body) = 69.05 + 168, 50 = 237.55[mm²]A_(Capsule − cap) = 75. + 137.2 = 212.2[mm²]A_(Pre − lockedcapsule) = 237.55 + 212.2 = 449.75[mm²]

TABLE 24 Capsuls Surface Area Parameter Body Cap A_(1/2 Sphere) [mm²]69.05 75.00 A _(Cylinder) [mm²] 168.50 137.20 A _(Segment) [mm²] 237.55212.20 A _(Pre-locked capsule) [mm²] 449.75

1-16. (canceled) 17: A process for preparing a polymer coated hard-shellcapsule, the process comprising: providing a hard-shell capsulecomprising a body and a cap in a pre-locked state, coating thehard-shell capsule in the pre-locked state with a coating solution,suspension, or dispersion comprising one or more (meth)acrylatecopolymers having a glass transition temperature from −10° C. to 115° C.as determined by differential scanning calorimetry (DSC) according toISO 11357-2:2013-05, to obtain a coating layer on the hard-shellcapsule, and optionally, drying the coated hard-shell capsule, wherein amaterial of the body and the cap is selected from the group consistingof ethyl ether of cellulose, methyl ether of cellulose, propyl ether ofcellulose, starch, and pullulan, wherein the coating layer is present inan amount of about 1 to 5.8 mg/cm², and wherein a dried film of thecoating solution, suspension, or dispersion having a thickness of 250μm, has an elongation at break of about 15 to 500%. 18: The processaccording to claim 17, wherein the material of the body and the capcomprises hydroxypropyl methyl cellulose. 19: The process according toclaim 17, wherein the one or more (meth)acrylate copolymers is selectedfrom the group consisting of a copolymer of methacrylic acid and ethylacrylate; a copolymer of methacrylic acid and methyl methacrylate; acopolymer of ethyl acrylate and methyl methacrylate; a copolymer ofmethacrylic acid, methyl acrylate, and methyl methacrylate; a mixture ofa copolymer of methacylic acid and ethyl acrylate, with a copolymer ofmethyl methacrylate and ethyl acrylate; and a mixture of a copolymer ofmethacrylic acid, methyl acrylate, and methyl methacrylate, with acopolymer of methyl methacrylate and ethyl acrylate. 20: The processaccording to claim 17, wherein the coating layer comprises a(meth)acrylate copolymer comprising polymerized units of 40 to 60% byweight of methacrylic acid and 60 to 40% by weight of ethyl acrylate.21: The process according to claim 17, wherein the coating layercomprises a (meth)acrylate copolymer comprising polymerized units of 60to 80% by weight of ethyl acrylate and 40 to 20% by weight of methylmethacrylate. 22: The process according to claim 17, wherein the coatinglayer comprises a (meth)acrylate copolymer comprising polymerized unitsof 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methylacrylate, and 20 to 30% by weight of methyl methacrylate. 23: Theprocess according to claim 17, wherein the coating layer comprises amixture of (meth)acrylate copolymers comprising polymerized units of 40to 60% by weight of methacrylic acid and 60 to 40% by weight of ethylacrylate; and a (meth)acrylate copolymer comprising polymerized units of60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methylmethacrylate; at a ratio from 10:1 to 1:10 by weight. 24: The processaccording to claim 17, wherein the coating layer comprises a mixture of(meth)acrylate copolymers comprising polymerized units of 5 to 15% byweight of methacrylic acid, 60 to 70% by weight of methyl acrylate, and20 to 30% by weight of methyl methacrylate; and a (meth)acrylatecopolymer comprising polymerized units of 40 to 60% by weight ofmethacrylic acid and 60 to 40% by weight of ethyl acrylate; at a ratiofrom 1:1 to 5:1 by weight. 25: The process according to claim 17,wherein the coating layer comprises 2-50% by weight of one or moreplasticizers. 26: The process according to claim 25, wherein the one ormore plasticizers is selected from the group consisting of alkylcitrate, glycerol ester, alkyl phthalate, alkyl sebacate, sucrose ester,sorbitan ester, glycerol, propylene glycol, and polyethylene glycol. 27:The process according to claim 17, wherein the coating layer comprises50 to 100% by weight of the one or more (meth)acrylate copolymers and 50to 0% by weight of pharmaceutical or nutraceutical excipients. 28: Theprocess according to claim 27, wherein the pharmaceutical ornutraceutical excipients comprises one or more detacking agents. 29: Theprocess according to claim 28, wherein the one or more detacking agentsis selected from the group consisting of Ca-stearate, Mg-stearate,glycerol monostearate, and talc. 30: The process according to claim 17,wherein the coating layer comprises an emulsifier. 31: The processaccording to claim 30, wherein an amount of the emulsifier is in a rangeof 1 to 30% by weight calculated based on a weight of the one or more(meth)acrylate copolymers. 32: The process according to claim 30,wherein the emulsifier is polysorbate
 80. 33: The process according toclaim 17, wherein the coating layer is present in an amount of about 2to 5 mg/cm².